Keywords: HEED, SEED, IVF, Hysteroscopy, Embryo implantation, Embryo transfer

Transcription

1 Hysteroscopic Embryo Transfer or Implantation Experience of a Decade: An Alternative Objective and Reliable Method for Embryo Transfer (HEED) and Implantation (SEED) Michael Kamrava 1*, Mei Yin 1 1 WC IVF Clinic, inc., 325 N Maple Drive, Unit 5731, Beverly Hills, CA 90210, USA. ABSTRACT Aims: Here we present our experience using HEED and SEED and describe these procedures in more detail along with a new look at the endometrial cavity and the placement of embryo transfer or implantation under direct visualization. Study design: Retrospective non randomized and uncontrolled case series. Place and Duration of Study: West Coast IVF Clinic, Inc. and LA IVF Lab, LLC, Beverly Hills, CA, USA, between June 2002 and June Methodology: Embryo transfer was done using a mini flexible hysteroscope with an articulating tip. This was accomplished by either placing the embryo gently on the surface of the endometrium (HEED) in 35 patients undergoing IVF, or embedding the embryo just beneath the endometrial surface (SEED) in 24 patient starts using egg donation. Once pregnancy was confirmed with a positive serum hcg, they were followed up with transvaginal ultrasounds and serial serum hcg s in the first trimester. They were then referred to their local obstetricians and final outcomes were recorded after deliveries. Results: There were a total of 35 patients in the early (days 2 or 3) embryo transfer group (HEED). We had 16 (46%) total pregnancies, which included 2 biochemical pregnancies, 2 ectopics, 5 spontaneous miscarriages, and 3 multiple pregnancies. There were 7 (20%) Live births. In the second group of patients with day 5 or 6 embryo implantations (SEED), there were a total of 24 patient starts, with 16(67%), 4, 0, 5, and 4 total, biochemical, ectopic and multiple pregnancies respectively. There were 7(29%) live births. Conclusion: Hysteroscopic embryo transfer or implantation may increase successful pregnancies and decrease risks and side effects from IVF procedures. Further prospective, controlled and randomized studies are needed to determine effectiveness of these procedures. Keywords: HEED, SEED, IVF, Hysteroscopy, Embryo implantation, Embryo transfer 1. INTRODUCTION Over the last 35 years since the birth of the first human IVF pregnancy major progress has been made in different components of IVF procedures [1-6]. However, there is a great difference of approximately 85% between normal embryo development and pregnancy rate

2 [7]. This failure rate suggests that the embryo transfer stage is a key step to successful live pregnancy rates in assisted reproductive technology (ART) [8]. Traditionally embryo transfer is done by using a catheter that is introduced into the uterus guided by a feeling of touch that is dependant on the individual operator s past experience. A fixed distance from uterine fundus and varying lengths of insertion into the uterine cavity have been suggested with or without the use of ultrasound, although a routine use of ultrasound to increase pregnancies remains controversial [9,11-14]. Other factors implicated in the low pregnancies from IVF include: non-tactile uterine contractions, embryos falling out of the uterine cavity into the cervix, bloody or mucus plugs on the catheter tip, bacterial contamination of the catheter, and embryos that were not expelled out of the transfer catheter [10]. Furthermore, other yet undiscovered factors responsible for embryo attachment and implantation are also of utmost importance in achieving pregnancies from healthy embryos [15-18]. Since our initial success with endoscopic embryo implantation (SEED) [19-21], endoscopic embryo transfers were subsequently extended to the earlier stages of embryo development, especially in patients with advanced age, or poor responders, for direct transfers onto the endometrium. 2. MATERIAL AND METHODS Prior to the procedures informed consent regarding traditional embryo transfer versus hysteroscopic embryo transfer or implantation was obtained from all patients. The techniques for the two procedures, HEED and SEED (Hysteroscopic Endometrial Embryo Deposition) have been previously described [19-21]. Uterine distention was achieved using nitrogen gas via a hysteroscopy insufflator. The catheter used in these procedures was initially made by Cook OB/GYN, Spencer, Indiana, USA and subsequently made by IVF Scientific, Beverly Hills, CA USA, (Figure 1). The loading catheter is shown in Figure1. Endometrial placement of embryos is shown in Figures 2, 3, and RESULTS The combined results are shown in Tables 1, 2 and 3. There were a total of 35 patients in the early (days 2 or 3) embryo transfer group (HEED). We had 16 (46%) total pregnancies, which included 2 biochemical pregnancies, 2 ectopics, 5 spontaneous miscarriages, and 3 multiple pregnancies. There were 7 (20%) Live births. In the second group of patients with day 5 or 6 embryo implantations (SEED), there were a total of 24 patient starts, with 16(67%), 4, 0, 5, and 4 total, biochemical, ectopic and multiple pregnancies respectively. There were 7(29%) live births. 4. DISCUSSION There has been little change in embryo transfer technique using a catheter to blindly guide by feel and touch into the uterine cavity and then ejecting the embryo(s). Gamete intrafallopian transfer (GIFT), zygote intra-fallopian transfer (ZIFT), pronuclear stage transfer and embryo intrafallopian transfer (EIFT) [22-29] require invasive surgical procedures done under general anesthesia. Although ultrasound guided ET was desired to improve successful pregnancy outcomes and reduce side effects, it has been received with mixed results [30-42]. It also requires simultaneous coordination of two professionals, the clinician who performs the transfer and the ultrasound technician [37]. Furthermore, with the transmyometrial technique, the needle has to go through the myometrium first, and then be inserted into the endometrium or released onto the endometrial surface. The procedure is more invasive than going through the natural opening of the cervix. Consistent and accurate positioning of the catheter would be difficult with the mobile uterus and hyperstimulated

3 ovaries. In addition, myometrial invasion would be more likely to produce involuntary uterine contractions and bleeding that although cannot be seen nor verified with high accuracy by ultrasound, could have deleterious effects on final pregnancy outcome [43,44]. In order to compensate in part for luteal phase defects and other yet undiscovered factors that may interfere with embryo adherence, penetration or implantation clinicians transfer more embryos. By mechanically inserting the embryo into the endometrium using SEED technique, problems associated with the maternal receptivity may become a moot point [18]. After the initial success with SEED [19], we focused our attention to a better prognostic group of patients, i.e. egg donors [20]. Hysteroscopic SEED virtually eliminated ectopic pregnancies (tubal, placenta previa, cervical, or heterotopic) from embryo transfers that occurred in approximately 8-10% of high risk pregnancies [11,45,46]. Lost embryos were also minimized as the embryo(s) was implanted into the endometrium and not left to float within the uterine cavity. Using the flexible mini-hysteroscope affords an objective and accurate confirmation of the placement of the embryo that is reliable and should make the procedure replicable with more consistent and improved results. In patients with advanced age, low ovarian reserve or poor responders, a day 2 or 3 embryo transfer using HEED technique is more desirable as the in vitro conditions may not be optimal for the extended culture survival of the embryos. In situations where there are many high quality embryos to choose from, allowing the embryos to reach the blastocyst stage prior to transfer has gained more acceptance [45,46]. This natural selection of the healthier embryos would make the final embryo selection for transfer easier and allow for a less number of embryos to be transferred[47,48]. This is compatible with our results where there were no multiple pregnancies from day 6 implantations (SEED) (Table 1). Hysteroscopic embryo transfer, whether by HEED or SEED, is objective and reproducible. Since involuntary uterine contractions are known to decrease embryo retention and implantation (43,44,49,50), using the endoscopic approach would be invaluable at detection of contractions prior to actual release of the embryo(s). In these situations embryo transfer is aborted and the embryo(s) are frozen and stored for future replacement under more favorable conditions. In addition, embryo transfer under direct visualization allows for visual confirmation of release of the very low volume of transfer fluid [8,51,52] and a more precise placement of embryo(s).the ability to visualize the uterine cavity through an endoscope at time of embryo transfer is particularly important in patients with uterine fibroids, adenomyosis and intrauterine adhesions as the flexible and articulating tip of the scope can be easily maneuvered in the gaseous space. In addition, multiple suitable areas for implantation can be identified (Fig 4). The disadvantage and risk of this technique is possible endometrial injury with the scope. Since the uterine cavity is distended prior to scope entry, the risk is less than blind and ultrasound guided transfers [53]. Additionally, direct visualization allows one to place the embryo at a different and non-traumatized location if endometrial injury is noted. The major drawback to its acceptance is that hysteroscopy will increase the total cost of the procedure. However, the small increase in cost is well worth the despair, agony and further additional cost of repeat IVF s to achieve a successful pregnancy. 5. CONCLUSION Hysteroscopic embryo delivery provides a visually confirmed technique for embryo placement. It allows for a targeted positioning of the embryo(s) which may increase live

4 delivery rate and decrease untoward side effects from embryo transfer. Hence, reductions in multiple pregnancies can be focused on selecting the healthiest single embryo for transfer. Attention to detail in loading the embryo(s) [21] and direct visual placement of embryo(s) away from both internal cervical os and the junction of endometrium with endosalpingeal epithelium (Fig. 4), will minimize ectopic pregnancies in various anatomical locations. SEED is especially appealing in patients with prior tubal pregnancies and failed IVF. Additionally, patients will feel more at ease because they can simultaneously see the procedure on a live video monitor while undergoing treatment. A quicker successful pregnancy outcome will also decrease the cost to the patient because it will decrease the number of attempts necessary using IVF procedures in order to achieve a successful singleton pregnancy [54]. ACKNOWLEDGEMENTS Supported by: West Coast IVF clinic, Inc. and LA IVF Lab, LLC, Beverly Hills, CA USA. The project was also partially supported by a generous funding from Organon. The authors wish to thank Soheila Kamrava, Michelle Kamrava, and Mitchell Kamrava for their invaluable support and understanding during preparation of this report. ABBREVIATIONS HEED: Hysteroscopic endometrial embryo transfer; SEED: Subendometrial embryo delivery. COMPETING INTERESTS Michael Kamrava is the inventor of KAM catheter and is a consultant to IVF Scientific, Inc. AUTHORS CONTRIBUTIONS Both authors read and approved the final manuscript. REFERENCES 1. Gardner DK et al. Culture and transfer of human blastocysts increases implantation rates and reduces the need for multiple embryo transfers. Fertil Steril 1998; 69(1): Dellenbach P et al. Transvaginal sonographically controlled follicle puncture for oocyte retrieval. Fertil Steril 1985; 44(5): Fateh M et al. Comparison of ultrasonographic transurethral and laparoscopic guided oocytes retrieval. Fertil Steril 1986; 46(4): Hamberger L et al. Laparoscopy versus ultrasound guided puncture for oocyte retrieval. Acta Eur Fertil 1986; 17(3): Ragni G et al. Echoguided transvaginal oocyte retrieval: effective and easy to learn technique. Acta Eur Fertil 1991; 22(2): Raziel A et al. Ultrasonographic-guided percutaneous transabdominal puncture for oocyte retrieval in a rare patient with Rokitansky syndrome in an in vitro fertilization surrogacy program. Fertil Steril 2006; 86(6):

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6 23. Asch RH et al. Oocyte donation and gamete intrafallopian transfer in premature ovarian failure. Fertil Steril 1988; 49(2): Balmaceda JP, Gonzales J, Bernardini L. Gamete and zygote intrafallopian transfers and related techniques. Curr Opin Obstet Gynecol 1992; 4(5): Cittadini E et al. Gamete intrafallopian transfer: different routes of transfer. Acta Eur Fertil 1988; 19(4): Frederick JL et al. Frozen zygote intrafallopian transfer: a successful approach for transfer of cryopreserved embryos. Fertil Steril 1994; 61(3): Pool TB et al. Zygote intrafallopian transfer as a treatment for nontubal infertility: a 2- year study. Fertil Steril 1990; 54(3): Thijssen RF et al. Successful pregnancy after ZIFT in a patient with congenital cervical atresia. Obstet Gynecol 1990; 76(5 Pt 2): Henriksen T et al. Pregnancy after translaparoscopic embryo intrafallopian transfer (EIFT). Acta Obstet Gynecol Scand 1987; 66(8): Allahbadia G.N et al. Embryo transfer using the SureView catheter-beacon in the womb. Fertil Steril 2010; 93(2): Flisser E, J.A. Grifo. Is what we clearly see really so obvious? Ultrasonography and transcervical embryo transfer--a review. Fertil Steril 2007; 87(1): Flisser E et al. Transabdominal ultrasound-assisted embryo transfer and pregnancy outcome. Fertil Steril 2006; 85(2): Grifo JA et al. Programmatic implementation of blastocyst transfer in a universitybased in vitro fertilization clinic: maximizing pregnancy rates and minimizing triplet rates. Fertil Steril 2007; 88(2): Lambers MJ et al. The position of transferred air bubbles after embryo transfer is related to pregnancy rate. Fertil Steril 2007; 88(1): Tiras B et al. Impact of embryo replacement depth on in vitro fertilization and embryo transfer outcomes. Fertil Steril 2010; 94(4): Anderson RE et al. Transvaginal ultrasound-guided embryo transfer improves outcome in patients with previous failed in vitro fertilization cycles. Fertil Steril 2002;77(4): Gergely RZ et al. Three dimensional/four dimensional ultrasound-guided embryo transfer using the maximal implantation potential point. Fertil Steril 2005; 84(2): Itskovitz-Eldor J et al. Assisted implantation: direct intraendometrial embryo transfer. Gynecol Obstet Invest 1997; 43(2): Kol S. Ultrasound-guided embryo transfer--a special role in patients with certain uterine defects. Fertil Steril 2008; 89(1): 260.

7 40. Aboulfotouh I et al. Firm versus soft embryo transfer catheters under ultrasound guidance: does catheter choice really influence the pregnancy rates? Fertil Steril 2008; 89(5): Abou-Setta AM et al. Among women undergoing embryo transfer, is the probability of pregnancy and live birth improved with ultrasound guidance over clinical touch alone? A systemic review and meta-analysis of prospective randomized trials. Fertil Steril 2007; 88(2): Miller KL, Frattarelli JL. The pre-cycle blind mock embryo transfer is an inaccurate predictor of anticipated embryo transfer depth. J Assist Reprod Genet 2007; 24(2-3): Biervliet FP et al. Transmyometrial embryo transfer and junctional zone contractions. Hum Reprod 2002; 17(2): Fanchin R et al. [Uterine contractions at the time of embryo transfer: a hindrance to implantation?]. Contracept Fertil Sex 1998; 26(7-8): Chang HJ, Suh CS. Ectopic pregnancy after assisted reproductive technology: what are the risk factors? Curr Opin Obstet Gynecol 2010; 22(3): Strandell A. Thorburn J, Hamberger L. Risk factors for ectopic pregnancy in assisted reproduction. Fertil Steril 1999; 71(2): Stillman RJ et al. Elective single embryo transfer: a 6-year progressive implementation of 784 single blastocyst transfers and the influence of payment method on patient choice. Fertil Steril 2009; 92(6): Sills ES, Palermo GD. Human blastocyst culture in IVF: current laboratory applications in reproductive medicine practice. Rom J Morphol Embryol 2010; 51(3): Kovacs GT. Which factors are important for successful embryo transfer after in-vitro fertilization? Hum Reprod Oct;14(10): Lesny P, Killick SR, Tetlow RL, Robinson J, Maguiness SD. Embryo transfer--can we learn anything new from the observation of junctional zone contractions? Hum Reprod Jun;13(6): Visser DS, Fourie FL, Kruger HF. Multiple attempts at embryo transfer: effect on pregnancy outcome in an in vitro fertilization and embryo transfer program. J Assist Reprod Genet 1993; 10(1): Marcus SF, Brinsden PR. Analysis of the incidence and risk factors associated with ectopic pregnancy following in-vitro fertilization and embryo transfer. Hum Reprod 1995; 10(1): Bodri D et al. Transvaginal versus transabdominal ultrasound guidance for embryo transfer in donor oocyte recipients: a randomized clinical trial. Fertil Steril 2011; 95(7): , 2268.e PGDIS. Guidelines for good practice in PGD: programme requirements and laboratory quality assurance. Reprod Biomed Online 2008; 16(1):

8 Table 1. Pregnancy outcomes from HEED. Day 2 Day 3 Transfer Transfer Combined Patients started Total Pregnancy/Started (46%) Biochemical Pregnancies Ectopic Pregnancies Spontaneous Abortions Multiple Pregnancies Live/Started 3 4 7(20%) Table 2. Pregnancy outcomes from SEED. Day 5 Day 6 Implantation Implantation Combined Patients started Total Pregnancy/Started 8(57%) 8(80%) 16(67%) Biochemical Pregnancies Ectopic Pregnancies Spontaneous Abortions Multiple Pregnancies Live/Started 4 (29%) 3 (30%) 7 (29%)

9 Table 3. Pregnancy outcomes from combined HEED and SEED. Combined Patients started 59 Total Pregnancy/Started 32 Biochemical Pregnancies 6 Ectopic Pregnancies 2 Spontaneous Abortions 10 Multiple Pregnancies 7 Live/Started 14(24%)

10 Figure Legends Figure 1. Flexible KAM hysteroscopic embryo delivery catheter (HEED or SEED), (IVF Scientific, Inc. Beverly Hills, CA, USA). Figure 2. Placement of embryo(s) under hysteroscopic guidance for HEED; arrow points to the tip of the catheter; catheter tip at 8 o'clock position. Figure 3C and D. Placement of embryo(s) under hysteroscopic guidance for SEED; arrow points to the tip of the catheter; catheter entry at 8 o'clock position. Figure 4. Endometrial places of embryo delivery.

11 Fig 1_KAM_Cath Fig2_HEED Fig3_SEED Fig4_Placement of embryo